Magnetic Brain Stimulation in Small Fiber Neuropathy

Transcranial Magnetic Stimulation for Pain Management in Small Fiber Neuropathy

Small fiber neuropathy (SFN) is a condition in which the smallest nerve fibers are damaged. This leads to severe pain and disturbances in the body's automatic functions. As a result, quality of life is often substantially reduced.

Pain is one of the main symptoms of small fiber neuropathy. Unfortunately, the effects of currently available pain medications are often disappointing and may be accompanied by unacceptable side effects. Although the smallest nerve fibers do not function properly in SFN, the brain also appears to play a role in the symptoms. Specialized brain imaging studies have shown that brain activity and certain neural connections differ between patients with SFN and healthy individuals. Therefore, the brain may also represent a suitable target for treatment.

In several chronic pain conditions, it has been demonstrated that stimulation of specific brain regions using magnetic pulses delivered through a specialized coil can reduce pain. This treatment can be administered using repetitive Transcranial Magnetic Stimulation (rTMS), a safe and non-invasive technique that is already available in the Netherlands for people with severe depression. The effectiveness of rTMS has never been investigated in patients with small fiber neuropathy. In addition, the pain-relieving effects of treatment are often temporary. Maintenance treatment may offer a potential solution to this problem.

Small fiber neuropathy (SFN) is a peripheral neuropathy dominated by invalidating neuropathic pain, leading to a substantial decline of quality of life (QOL). Pharmacological treatment is often ineffective and causes debilitating side effects. Interestingly, while constituting a peripheral nerve condition, SFN is also characterized by changes in brain network connectivity as demonstrated by structural and functional brain imaging, making the brain a promising treatment target for SFN. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has been proven to be effective in chronic neuropathic pain treatment, by inducing changes in cortical excitability. However, the number of neuropathy patients that has been studied is limited, and induced analgesic effects were rather short-lived in duration.

We hypothesize that rTMS is an effective treatment strategy for neuropathic pain in SFN compared to sham stimulation. The primary objective is to evaluate the efficacy of rTMS for pain alleviation in SFN patients. Secondary objectives are to assess the effect of providing repeated maintenance rTMS treatment on prolonged pain relief, and to study the effect of rTMS on pain intensity, pain qualities, other SFN-related complaints, daily functioning and QoL, as well as safety features of rTMS in SFN.

Inclusion Criteria:

• 18 years of age or older.
• Skin-biopsy proven idiopathic SFN.
• Pain intensity (maximum pain) rated ≥5 on the PI-NRS, that must have existed for at least 12 weeks before the study.
• Written informed consent.

Exclusion Criteria:

• Signs of large nerve fiber dysfunction (i.e., weakness, loss of vibration sense, hyporeflexia or areflexia, abnormal nerve conduction studies).
• Identifiable underlying cause of SFN (diabetes, SCN9A/SCN10A/SCN11A mutations, hypothyroidism, vitamin B12 deficiency, monoclonal gammopathy, alcohol abuse (more than 5 IU/day), malignancies, or drugs that cause neuropathy).
• Implanted ferromagnetic devices or other magnetic-sensitive metal implants close to the magnetic coil.
• History of epilepsy.
• Using pain medication that has changed in the 30 days prior to randomization.
• Pregnancy.
• Mentally challenged subjects unable to give independent informed consent.
• Clinically significant or unstable psychiatric disorder including major depression, (history of) substance abuse and other major disorders in accordance with DSM-V,